Crimean-Congo Hemorrhagic Fever Virus Suppresses Innate Immune Responses via a Ubiquitin and ISG15 Specific Protease

• DOI: 10.1016/j.celrep.2017.08.040
• Publication Date: 2017-09-05T16:15:14Z
• Authors: Florine E.M. Scholte; Marko Zivcec; John V. Dzimianski; Michelle K. Deaton; Jessica R. Spengler; Stephen R. Welch; Stuart T. Nichol; Scott D. Pegan; Christina F. Spir...; Éric Bergeron
• Keywords: 0301 basic medicine; QH301-705.5; Virus Replication; interferon stimulated gene-15; reverse genetics; 03 medical and health sciences; ubiquitin; Humans; Biology (General); innate immunity; Ubiquitins; virus replication; Ovarian Neoplasms; ubiquitin specific protease; Deubiquitinating Enzymes; Ubiquitin; interferon; 3. Good health; Hemorrhagic Fever Virus; Hemorrhagic Fever Virus, Crimean-Congo; Crimean-Congo; Crimean-Congo hemorrhagic fever; Bunyavirus; Cytokines; Female; Ubiquitin-Specific Proteases

Antiviral responses are regulated by conjugation of ubiquitin (Ub) and interferon-stimulated gene 15 (ISG15) to proteins. Certain classes of viruses encode Ub- or ISG15-specific proteases belonging to the ovarian tumor (OTU) superfamily. Their activity is thought to suppress cellular immune responses, but studies demonstrating the function of viral OTU proteases during infection are lacking. Crimean-Congo hemorrhagic fever virus (CCHFV, family Nairoviridae) is a highly pathogenic human virus that encodes an OTU with both deubiquitinase and deISGylase activity as part of the viral RNA polymerase. We investigated CCHFV OTU function by inactivating protease catalytic activity or by selectively disrupting its deubiquitinase and deISGylase activity using reverse genetics. CCHFV OTU inactivation blocked viral replication independently of its RNA polymerase activity, while deubiquitinase activity proved critical for suppressing the interferon responses. Our findings provide insights into viral OTU functions and support the development of therapeutics and vaccines.